The long term goal of this project is to further elucidate mechanisms of the control of respiration. Specifically, this project focuses on control of breathing in hypoxia and mechanisms producing the time-dependent increase in ventilation on exposure to prolonged hypoxia, termed acclimatization to hypoxia (VAH) and the mechanisms maintaining the hyperventilation on termination of the exposure to hypoxia (de-acclimatization). Much of the project deals with mechanisms causing increased sensitivity of O2 sensing organs, the carotid bodies (CBs), to hypoxia during VAH. The specific aims are: 1. To determine if inhibitory CB dopamine (DA) receptors are down-regulated during VAH. 2. To determine if excess DA provided to the CB will prevent VAH. 3. To determine if inhibitory DA mechanisms can be artificially induced to accelerate VAH. 4. To determine if excitatory DA receptors in the CB are up-regulated during VAH. 5. To determine if nitric oxide (NO) is an inhibitory modulator of the goat CB. 6. To determine if the NO synthesizing enzyme in the CB, nitric oxide synthase (NOS), is inhibited during VAH resulting in increased sensitivity of the CB to hypoxic stimulation. 7. To test the hypothesis that central chemoreceptors are reset during VAH and thus responsible for maintaining hyperventilation during de-acclimatization. Unique awake goat preparations that allow assessment of drug effects at the CB and isolation of blood gas stimuli to the CB will be used. These studies will be supported by recordings of CB afferent neural activity in anesthetized goats. The function of DA receptors and chemical mediators in the CB will be assessed under normal O2 levels and during acute and prolonged hypoxia using histochemistry, immunocytochemistry, autoradiography and in situ hybridization. These studies will provide new information on function of the CBs, which are important in defending the individual against hypoxic states by causing reflex increased breathing. Under certain pathologic conditions CB stimulation may contribute to dyspnea. Knowledge of their function is critical to understanding of the respiratory pathophysiology of diseases characterized by acute and chronic hypoxia such as chronic obstructive pulmonary disease and sleep apnea. The studies will also add to our understanding of the control of respiration in normal individuals exposed to hypoxia, e.g., ascent to high altitude.